PPARγ agonists promote differentiation of cancer stem cells by restraining YAP transcriptional activity
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Upal Basu-Roy1,*, Eugenia Han2,*, Kirk Rattanakorn1, Abhilash Gadi1, Narendra Verma1, Giulia Maurizi1, Preethi H. Gunaratne3, Cristian Coarfa4, Oran D. Kennedy5, Michael J. Garabedian1,2, Claudio Basilico1,2 and Alka Mansukhani1,2
1 Department of Microbiology, NYU School of Medicine, New York, NY, USA
2 Perlmutter Cancer Center, Langone Medical Center, New York, NY, USA
3 Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA
4 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
5 Department of Orthopaedic Surgery, NYU School of Medicine, New York, NY, USA
* These authors have contributed equally to this work
Alka Mansukhani, email:
Keywords: osteosarcoma, thiazolidinediones, cancer stem cells, osteoblast lineage, adipocyte
Received: July 15, 2016 Accepted: August 01, 2016 Published: August 12, 2016
Osteosarcoma (OS) is a highly aggressive pediatric bone cancer in which most tumor cells remain immature and fail to differentiate into bone-forming osteoblasts. However, OS cells readily respond to adipogenic stimuli suggesting they retain mesenchymal stem cell-like properties. Here we demonstrate that nuclear receptor PPARγ agonists such as the anti-diabetic, thiazolidinedione (TZD) drugs induce growth arrest and cause adipogenic differentiation in human, mouse and canine OS cells as well as in tumors in mice. Gene expression analysis reveals that TZDs induce lipid metabolism pathways while suppressing targets of the Hippo-YAP pathway, Wnt signaling and cancer-related proliferation pathways. Significantly, TZD action appears to be restricted to the high Sox2 expressing cancer stem cell population and is dependent on PPARγ expression. TZDs also affect growth and cell fate by causing the cytoplasmic sequestration of the transcription factors SOX2 and YAP that are required for tumorigenicity. Finally, we identify a TZD-regulated gene signature based on Wnt/Hippo target genes and PPARγ that predicts patient outcomes. Together, this work highlights a novel connection between PPARγ agonist in inducing adipogenesis and mimicking the tumor suppressive hippo pathway. It also illustrates the potential of drug repurposing for TZD-based differentiation therapy for osteosarcoma.
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